The behavioral, biochemical, and histologic effects of tissue implants in rodent and primate models of parkinsonism is being studied. The grafts which have been examined include fetal and adult dopaminergic and nondopaminergic tissues. There is some behavioral improvement with any operative trauma to the caudate, whether or not a graft is placed. Generally, fetal tissue grafts (dopaminergic or nondopaminergic) lead to a much greater degree of recovery than adult tissue grafts or trauma alone. The histologic observation of dopaminergic fiber ingrowth (sprouting) in all these animals suggests that the improvement is mediated through a neurotrophic interaction. We are trying to determine the cell-to-cell interaction which leads to new growth of fibers from an adult neuron, using in vivo and in vitro methods. Two major areas of emphasis are: what cascade of events in the host after trauma leads to sprouting and why does fetal tissue enhance the recovery (even nondopaminergic tissue). To identify areas of the brain that are involved in host dopaminergic sprouting a series of experiments injecting anterograde and/or retrograde tracers were performed. The dopaminergic cells in the ventral tegmental area and the periolfactory area seems to be involved in the sprouting response. Another area of investigation addresses the question of how similar is the dopaminergic cell loss in the midbrain of idiopathic parkinsonian patients to cell loss in the monkeys treated with MPTP. We were able to identify anatomic subregions in the midbrain of parkinsonian patients still containing the dopaminergic cells. These areas are almost identical to the areas that are preserved in parkinsonian monkeys, suggesting that indeed there are dopaminergic cells in the parkinsonian brains that may be a source for the graft-induced host sprouting. The experiments included implantation of fetal and term amnion into hemiparkinsonian monkeys (solid tissue into preformed cavities), cell suspension implants of term amnion into rats, IL-1 slow-release polymers implants in hemiparkinsonian rats and monkeys. To further investigate the host response to tissue implantation, we are now using direct intrastriatal infusion of chemicals known to be released by inflammatory cells. Effects of direct intrastriatal infusion of chemicals known to be released by inflammatory cells. Effects of direct intrastriatal infusion of trophic factors as basic FGF, IGF-1, laminin, PDGF and IL-1 on the host dopaminergic system is now being studied in hemiparkinsonian rats. These animals displayed histologic signs of sprouting from the remaining dopaminergic neurons. Experiments on delivering trophic factors into hemiparkinsonian monkeys is underway.